Regulation of Brain IL-1 & Sickness Responses Following E.coli Challenge

描述（由申请人提供）：促炎细胞因子在大脑中对改变行为和内分泌反应有强有力的影响。促炎细胞因子水平升高介导许多行为和内分泌反应，包括外周免疫挑战，暴露于一些身体/心理压力源，脑损伤和中枢炎症如阿尔茨海默病，帕金森病和多发性硬化症。虽然脑细胞因子升高的生物学效应已经被很好地表征，但调节脑细胞因子产生的机制在很大程度上仍然未知。本研究的目的是研究外周免疫攻击后脑细胞因子的诱导和抑制机制，并确定这种调节在各种行为和内分泌反应中的生理重要性，如发烧、食物/水摄入量减少、学习/记忆受损和下丘脑-垂体-肾上腺（HPA）轴的激活。我们实验室最近的数据表明，肾上腺素能受体在脑细胞因子的诱导中起着重要作用，并且在不同的大脑区域受到外周大肠杆菌（E. coli）的攻击后，中央给药肾上腺素能受体拮抗剂可阻断或减弱细胞因子的产生。有趣的是，肾上腺素能受体仅介导位于孤立束核（NTS）的去甲肾上腺素能神经元支配的脑区产生脑细胞因子，而不介导位于蓝斑（LC）的去甲肾上腺素能神经元支配的脑区产生脑细胞因子。这些数据支持了先前发表的研究成果，即在免疫刺激后，NTS神经元被迅速而有力地激活，而LC神经元只有一小部分被激活。此外，我们提出LC神经元在免疫应答过程中的激活可以抑制NTS活性。这一假设得到了以下观察结果的支持：刺激LC神经元抑制NTS活性，我们的初步数据表明，在大肠杆菌攻击NTS投射部位后，LC投射的病变会导致细胞因子的过量产生。这些数据导致我们目前的假设需要在本提案中进行验证，即在免疫挑战期间，NTS中的去甲肾上腺素能神经元的激活通过肾上腺素受体的激活诱导离散脑区域的细胞因子产生，而在免疫反应期间LC神经元的激活有助于抑制NTS的活性。

DESCRIPTION (provided by applicant): Pro-inflammatory cytokines have potent effects in the brain on altering behavioral and endocrine responses. Elevated levels of proinflammatory cytokines mediate many of the behavioral and endocrine responses observed following a variety of stimuli including peripheral immune challenge, exposure to some physical/psychological stressors, brain injury, and central inflammatory conditions such as Alzheimer's, Parkinson's, and multiple sclerosis. While the biological effects of elevated brain cytokines have been well characterized, the mechanisms that regulate brain cytokine production remain largely unknown. The aims of this proposal are to examine the mechanisms that regulate both the induction and inhibition of brain cytokines following a peripheral immune challenge, and establish the physiological importance of this regulation on various behavioral and endocrine responses such as fever, decreased food/water intake, impaired earning/memory, and activation of the hypothalamus-pituitary-adrenal (HPA) axis. Recent data from our laboratory demonstrate that ¿-adrenoceptors play an important role in the induction of brain cytokines, and that central administration of a ¿-adrenoceptor antagonist blocks or attenuates cytokine production following a peripheral Escherichia coli (E. coli) challenge in distinct brain areas. Interestingly, ¿-adrenoceptors only mediate brain cytokine production in brain areas innervated by noradrenergic neurons located in the nucleus of the solitary tract (NTS), and not in brain areas largely innervated by noradrenergic neurons located in the locus coeruleus (LC). These data support previously published work demonstrating that following immune stimuli, NTS neurons are rapidly and robustly activated, while only a subpopulation of LC neurons become activated. Furthermore, we propose that activation of LC neurons during an immune response function to inhibit NTS activity. This hypothesis is supported by observations that demonstrate stimulation of LC neurons suppresses NTS activity, and our preliminary data that lesions of LC projections results in exaggerated cytokine production following E. coli challenge in NTS projection sites. These data lead to our current hypothesis to be tested in this proposal that during an immune challenge activation of noradrenergic neurons in the NTS induce cytokine production in discrete brain areas via activation of ¿-adrenoceptors, while activation of LC neurons during an immune response serve to inhibit NTS activity.